The mechanism of activation of pain sensory endings has been difficult to study in vivo for two reasons. The nerve endings are small and generally inaccessible for intracellular microelectrode recording, and the cellular and fluid environment of these endings, which can be altered by noxious stimuli, is difficult to control. When primary sensory neurons are grown in dissociated-cell cultures in the virtual absence of other cell types, their neurites are directly accessible to the stimulus and electrical events occurring the neurites can be recorded in the cell body. In preliminary studies I have found that some neurons in these cultures display properties of primary pain sensory neurons in vivo: they are sensitive to low concentrations of capsaicin and bradykinin, and they contain substance P. The specific aim of this proposal is to study such neurons in the following ways (all potentially easier in such cultures than in vivo): 1. study electrophysiologically the sensitivity to algesics, modulators and analgesics, known to affect pain neurons in vivo and determine the ionic mechanism(s) of action of these compounds; 2. identify by a combinations of electrophysiological and immunohistochemical methods the peptides present in these putative pain neurons; 3. compare putative pain neurons from each of three different types of sensory ganglia (dorsal root, trigeminal and nodose) in terms of sensitivity to various algesics, modulators and analgesics and the presence of specific peptides. By increasing our understanding of the basic cell biology of pain reception, this study may eventually lead to improved relief or management of pain, a major clinical symptom.